Category: Historical studies of disease

This is the sixth of 16 student posts, guest-authored by Anna Lyons-Nace.

Natural…unprocessed…raw. These terms are often used by consumers, nutritionists and health experts to denote the most healthful, high-quality food options available for consumption. However, when pertaining to the recent increasing trend in raw milk consumption, can consumers be confident that they are choosing the safest and most healthful option? Statistical data and health studies would suggest otherwise.

Before we delve into the discussion any further, we should first establish what is considered raw milk and what is not raw. Raw milk is considered any animal milk, most often from cows, sheep and goats, which is not pasteurized, but still utilized for human consumption. Keep in mind that raw milk can also be used for producing other dairy products such as cheese and yogurt. Raw milk may also undergo a straining process, but it is otherwise unprocessed. Sources of raw milk are typically local farming operations. In fact, the interstate sale of raw milk for direct consumption has been prohibited in the U.S. by federal law since 1987, due to safety concerns regarding shelf life and disease risks. However, there are many states that allow the intrastate sale of raw milk, while a few states prohibit it completely. This means that the vast majority of what we see in our local grocery stores will have undergone the process of pasteurization, which will be clearly stated on the label. Pasteurization involves heating the milk to very specific temperatures for short time frames in order to kill potentially harmful germs. Pasteurization was introduced in the U.S. during the first part of the 20th century, at a time when millions of people were contracting life-threatening illnesses such as typhoid, diphtheria and tuberculosis, often through milk consumption. Applying the simple process of pasteurization, along with other health advances, led to a dramatic decline in such diseases, and is considered a major public health triumph. Decreasing or eliminating potentially harmful microbes through pasteurization, not only makes the product safer for consumers, it also increases shelf life.

So why is raw milk becoming a sought after commodity for many consumers? This can probably be attributed to such things as a general increase in societal demand for whole, natural and sustainable food products; as well as the perceived benefits of the milk itself. Raw milk drinkers claim that the unpasteurized product is higher in nutrients, protective enzymes and immune boosting probiotics, and can help treat a variety of ailments from asthma to gastrointestinal disorders. Supporters also claim that pasteurization is the cause of milk allergies and lactose intolerance. It is important to note that these claims remain largely unsubstantiated by published scientific studies. In many cases these claims have been categorically refuted by direct scientific evidence. The Food and Drug Administration (FDA) frankly states that “research shows no meaningful difference between the nutrient content of pasteurized and unpasteurized milk”. Science has also shown that most enzymes of concern by advocates are not altered by pasteurization. For those with allergy concerns, medical experts and research agrees that it is the proteins naturally present in milk (both raw and pasteurized) that are the cause of allergic reactions to milk and have no relationship to the pasteurization process. In regards to lactose intolerance, it needs to be understood that lactose intolerance is a genetic error of metabolism that some people are born with, and there is lactose present in both raw and pasteurized milk. So unfortunately for the lactose intolerant, raw milk is not the solution. As for probiotics, milk does not naturally contain probiotics; so if they are detected in the raw milk they are likely from another source such as air exposure or fecal contamination. But the good news is that we as consumers have many, safer options for experiencing the benefits of probiotics, including yogurt with active cultures and over the counter supplements.

Now that we have explored some of the common myths surrounding raw and pasteurized milk, it is most important to discuss the reality of the risks involved with raw milk consumption. Real world case studies, as well as research by such reputable organizations as the Centers for Disease Control and Prevention (CDC) and the FDA, consistently show that the risks of raw milk consumption far outweigh any real or perceived benefit. A 13 year study by the CDC showed raw milk and raw milk products are 150 times more likely to cause a disease outbreak than are pasteurized dairy products. These risks come in the form of a long list of disease causing germs that can contaminate dairy products, and are the reason that pasteurization was instituted in the first place. Some of the more significant contaminants that can be present in raw milk include such pathogens as Salmonella, E. coli, Listeria, and Campylobacter. These pathogens can cause a variety of symptoms, but most commonly produce gastrointestinal illness such as vomiting and diarrhea that can range from mild forms to fatal illnesses. The most vulnerable to becoming sick from drinking raw milk include babies, young children, those with weakened immune systems and pregnant women. But “healthy” people can become ill as well, and there are many documented cases. Data collected by the CDC from 1998-2009 documented 93 disease outbreaks due to raw milk and raw milk product consumption. These outbreaks caused 1,837 illnesses, 195 hospitalizations, and 2 deaths. It is important to note that for every case that is reported and diagnosed, there are many illnesses that go unreported, which means these case numbers in reality are certain to be much higher. The most recently reported outbreak occurred in Oregon this past April. The outbreak involved 19 people, 15 of which were children, with 4 of the children ending up in the hospital undergoing treatment for kidney failure. Eleven of the cases were confirmed to have been caused by a very dangerous strain of E. coli that was traced back to a dairy farm that supplied the families with raw milk. In reflecting on outbreaks such as these, it is important to remember that these illnesses are preventable. But hopefully, these sad cases will also serve to educate us as consumers, so that we can make informed and healthy choices for ourselves and our families.

Murine typhus has been in the news recently in Austin, TX, where in May of this year, two people were found to be positive and one died. This rings a number of alarm bells for me, since I live in Texas, and specifically in Austin. I know of another Austin veterinarian who got sick with murine typhus in 2008, when it was first noticed in Austin and investigated by the CDC. I was also working as a relief vet at the Town Lake Animal Center, the municipal shelter, and at the Austin Humane Society, the main nonprofit adoption shelter which has a feral cat Trap-Neuter-Return surgery clinic, when the CDC investigators came to Austin. They collected blood samples on local animals and also fleas. Of course, at that time I wasn’t particularly interested in public health, just shelter medicine, and it didn’t really register. Now I wish I could’ve gone back and tagged along to see more of what they were doing!

Murine typhus is an odd and off the radar disease. It doesn’t help that murine and typhus are both words with multiple meanings. Murine is a word that refers to mice, in Latin, murinus, or mouse, in Latin, mus. It is also a type of eye drops and also a brand of ear wax remover. How putting mice in your eyes or ears helps them is a mystery to me. Murine also sounds very similar to marine, so it’s not unreasonable to start picturing typhus near the ocean, which is an odd coincidence, since murine typhus actually occurs primarily in coastal areas.

Typhus itself is a confusing word. It comes from the Greek, and means hazy, which is how your brain feels if you’re infected. It is not the same as typhoid fever, which is caused by Salmonella typhi, a bacteria that can cause food borne illness resulting in diarrhea and vomiting. This is not that.

The typhus we are interested in is a tiny bacteria from the family Rickettsia. And of course there is more than one type of typhus, to confuse the issue further. Epidemic typhus is the ancient disease that has been a major player in history. It was first noted in the Spanish blockade of Granada in 1489, and then killed more of Napoleon’s army than the Russians. This is Rickettsia prowazekii, which is carried on lice and affects humans. This is the typical typhus. If you ever read just “typhus” it is referring to this type of typhus. It has also been called jail fever, since many old jails were breeding grounds for lice, and the prisoners were more likely to die of infection than be hung for their misdeeds. This typhus can cause a rash, fever, severe headache, joint pain, kidney failure, delirium, stupor, and even death in 10-60% of cases if it’s not treated. A blood test will show if there are antibodies to typhus if you go to your doctor with these signs. There is an effective treatment, a course of antibiotics that kills the rickettsia, and supportive care depending on how far along the disease had progressed. It is possible for the agent to go underground, and then reappear later in life. Then it is called Brill-Zinsser disease and is often a very mild form of epidemic typhus, still treated with antibiotics.

The typhus that showed up in Austin is murine typhus, also called Rickettsia typhi, and it is carried on fleas and primarily affects rats. This is also called endemic typhus because it is pretty much always present on rats in the environment. Humans historically get it as a side product of coming into contact with rats carrying the infected fleas. This disease is usually not as severe as epidemic typhus, but can still cause all the same signs and symptoms, and rarely can lead to death if not treated. Less than 2% die of murine typhus if it is not treated with antibiotics.

Murine typhus has a worldwide distribution, but in the United States it is usually seen near coastal areas in California, Hawaii, and Texas. The 2008 cases were odd that they were in Austin, in central Texas. In the previous 25 years, there had only been four cases total. In 2008 there were 13 cases in the four months from March to July, and a total of 33 cases by October. Of these, 70% of the people infected were hospitalized with myalgia, severe headache, and fever, and the most severe cases were treated for pneumonia, kidney failure, and coagulopathy. There were no deaths. This outbreak showed that aside from the normal rat-flea cycle, there are likely other cycles that involve domestic and feral cats, opossums, dogs, and the fleas that live on them. And consequently, the fleas that live on domestic cats and dogs then live in the yards and homes of their owners, and then can live on the owners themselves.

The cases were clustered in the central Austin area, with a large percentage coming from one zip code that contains a large portion of the exceedingly popular Town Lake Hike and Bike Trail used by over 20,000 people daily, and the smaller but more wild Shoal Creek Trail. There have been reports of coyote sightings and suspected killings of family pets in this zip code. So there is ample space for wildlife within this urban environment. This also means there are plenty of hosts for fleas. And Austin in general and this neighborhood in particular is known for a slightly hippy, crunchy granola lifestyle preferring organic and natural everything, with easy access to the outdoors and hiking trails. It is not surprising this outbreak occurred in this area.

So what does all this mean? Diseases which were previously uncommon are now becoming more common due to changes in lifestyle. People want to live close to nature and have trails to walk their dogs. There is nothing wrong with that. It’s the parasite hitchhikers their pets pick up and bring home that’s the problem. And changes in behavior where dogs are now not only in the house, but often in the bed with their owners, means that those fleas have a chance to bite humans. That doesn’t mean you shouldn’t walk your dog on the trail. But it does mean you need to use protection. Spray yourself and your clothes with a flea killing insecticide such as DEET when out walking. Wear boots, long pants, and long sleeved shirts. Use appropriate flea control on your pets. Kill fleas in your yard or home with appropriate premises control measures. It’s great to be one with nature, you just don’t want that nature to bite back with a case of murine typhus.

As good news surfaces regarding a new (well, old) potential drug to help combat malaria–a drug already used to treat river blindness–KeithB and Phil Scheibel alerted me to another old malaria fighter featuring Dopey, Sneezy, and the whole gang:

While “flesh-eating infections” caused by the group A streptococcus (Streptococcus pyogenes) may grab more headlines today, one hundred and fifty years ago, the best known and most dreaded form of streptococcal infection was scarlet fever. Simply hearing the name of this disease, and knowing that it was present in the community, was enough to strike fear into the hearts of those living in Victorian-era United States and Europe. This disease, even when not deadly, caused large amounts of suffering to those infected. In the worst cases, all of a family’s children were killed in a matter of a week or two. Indeed, up until early in the 20th century, scarlet fever was a common condition among children. The disease was so common that it was a central part of the popular children’s tale, The Velveteen Rabbit, written by Margery Williams in 1922.

Malaria is one of mankind’s most ancient scourges. A century after the discovery of its cause, various species of the parasite Plasmodium, humanity still remains in its deadly grip in many areas of the world. Malaria is estimated to have caused 225 million illnesses and almost 800,000 deaths in 2009, making it one of the top infectious disease killers. Many of these deaths occurred in children under the age of five.

Shah traces the history of malaria from the introduction of the parasite into the human population to modern-day controversies about malaria treatment, research, and funding. It’s a fast-paced read; informative but never dry. Indeed, Shah makes much use of metaphor; sometimes, to the detriment of the scientific narrative, in my opinion. However, that’s more of a minor issue to me.

Shah begins the book with an anecdote about her own childhood as an American visiting her relatives in India; sleeping under a bed net while her cousins sleep in the open, fearing mosquitoes, and India, and being ashamed of her fears. She notes later that, when her family hears she is writing a book about malaria, they ask her why–to them, it seems as silly as writing a book about the common cold. Shah notes this several times throughout the book–for example, explaining that many in malaria-endemic regions, people would rather use their bednets for fishing than to protect from mosquitoes, so while programs which deliver such nets can tout high numbers of bednets distributed it doesn’t necessarily mean that everyone who receives one is using them correctly.

Indeed, much of the book is spent discussing the limitations and missteps of anti-malarial programs, past and present, from issues of mosquito resistance to pesticides, to parasite resistance to chemotherapy. Another repeated thread is political will, or lack thereof, in anti-malarial programs, and the ping-pong that is played by many funding agencies. When programs demonstrate success and malaria is reduced, there is little will to continue such programs–which may be hampered in any case by the emergence of resistant mosquitoes or parasites. It’s a messy business, and today’s programs don’t seem to be much better off than those carried out in the previous century.

Shah’s book is a thoughtful read for anyone interested in global health–not only for the history of Plasmodium‘s detection and eventual proof as the cause of malaria (after many false starts), but also for the thoughtful descriptions of global health programs carried out by outsiders throughout the decades, and possible ways to change these and avoid repeating the mistakes already made by predecessors.

As with many infectious diseases, there are potential lingering sequelae of infection, which can occur weeks to years after the acute infection has cleared up. Like almost 800 others involved in this outbreak, the woman who unwittingly infected others via food developed hemolytic uremic syndrome, or HUS. We now know that the most common cause of HUS are bacteria such as STEC (“shiga toxin-producing E. coli“); the “shiga toxin” that they produce inhibits protein synthesis in the host and cause cell death. This can have systemic effects, and leads to clotting in affected organs–most commonly the kidneys, but other organs can also be affected. Dialysis may be necessary, and the infection can lead to kidney failure and the need for organ transplantation. There is already concern that, because of the huge numbers of HUS cases, many patients will have long-term kidney damage, including the potential need for additional organs (and possibly, re-vamping the way donations are made as well):

In previous E. coli outbreaks, up to half of patients who developed the kidney complication were still suffering from long-term side effects 10 to 20 years after first falling sick, including high blood pressure caused by dialysis.

In addition to possible kidney problems, people who have survived serious E. coli infections may also suffer from neurological damage, as the bacteria may have eaten away at blood vessels in the brain. That could mean suffering from seizures or epilepsy years after patients recover from their initial illness.

While it’s common knowledge in the medical community now that STEC can lead to HUS, which can lead to chronic kidney issues, for many years, the link between E. coli and HUS was obscured. HUS first appears in the literature in 1955, but the link to STEC wasn’t confirmed until the early 1980’s. In the interim, myriad viruses and bacteria were examined, as well as genetic causes. (There are cases of HUS caused by host mutations and other etiologies, but they are much less common than HUS caused by STEC and related organisms). I’ll delve into the history of HUS and look at a few studies which examined alternative hypotheses of causation, until finally STEC was confirmed as the causative agent. I’ll also discuss what this means as far as discovering infectious causes of other “complex” and somewhat mysterious diseases whose causes are unknown, as HUS was a mere 30 years ago.

Part Two

The epidemiology of hemolytic uremic syndrome (HUS) was murky for several decades after it was first defined in the literature in 1955. In the ensuing decades, HUS was associated with a number of infectious agents, leading to the general belief that it was a “multifactorial disease”–one that had components of genetics and environment, much like we think of multiple sclerosis today, for example.

Several HUS outbreaks made people think twice about that assumption, and look deeper into a potential infectious cause. A 1966 paper documented the first identified outbreak of HUS, which occurred in Wales. The researchers examined a number of possible environmental factors the patients may have had in common–including food, water, and various toxins–but came up empty. They sum up:

Since it is almost invariably preceded by a gastrointestinal or respiratory illness, it seems probable that it represents a response to an infection. Although Gianantonio et al. (1964) have identified one possible causative virus, it may be that various infective agents can initiate the syndrome.

This idea held throughout the next 20-odd years, as numerous studies looked at both environmental and genetic effects that may be leading to HUS. A 1975 paper examined HUS in families, suggesting that there may be two types of HUS (which we now know to be true–the genetic form is less often associated with diarrhea, and tends to have a worse prognosis as I mentioned yesterday). But still, no definitive cause for either.

There were also a number of studies testing individuals for many different types of pathogens. A 1974 paper enrolled patients in the Netherlands between 1965 and 1970, but one of the inclusion criteria was a “history of a prodromal illness in which gastrointestinal or respiratory tract symptoms were present.” The respiratory tract symptoms are mentioned in a number of papers, and were probably a red herring that sent people in search of the wrong pathogens for awhile. In this particular paper, they examined children for infection with a number of viral and bacterial pathogens, using either culture or serological methods (looking for antibodies which may suggest a recent infection). In that portion of the paper, they note a possible association with adenoviruses, but state that the data don’t support a bacterial infection–a viral etiology was deemed more likely. Regarding basic epidemiology, they did note a few small clusters of cases in families or villages, as well as a peak in cases in spring/summer–as well as an increasing number of cases from the first year of their study to the last. The epidemiology of HUS was starting to become clearer, and the syndrome appeared to be on the rise.

Even as additional case reports occasionally targeted foods as a precursor to HUS outbreaks, it wasn’t until the late 1970s and early 1980s that HUS really started to come into focus. In 1977, a paper was published identifying the “Vero toxin”–a product of E. coli that caused cytotoxicity in Vero cells (a line of African green monkey kidney cells, commonly used in research). Researchers were closing in.

Part Three

I left off yesterday with the initial discovery of “Vero toxin,” a toxin produced by E. coli (also called “Shiga toxin” or “Shiga-like toxin”). Though this may initially seem unconnected to hemolytic uremic syndrome (HUS), the discovery of this cytotoxin paved the way for a clearer understanding of the etiology of this syndrome, as well as the mechanisms by which disease progressed. By the early 1980s, several lines of research pointed toward E. coli, and particularly O157:H7, as the main cause of HUS.

A 1982 Centers for Disease Control and Prevention MMWR report found a rare E. coli serotype, O157:H7, associated with hemorrhagic colitis following consumption of hamburgers. Similar results were reported in a 1983 Lancet paper, which found serotype O157 among their collection of verotoxin-producing strains. Another paper that same year from a Canadian group showed that O157:H7 was the second most common cytotoxic strain in their collection of over 2,000 E. coli isolates. The most common was serotype O26–more on that below. This paper also discussed an outbreak of hemorrhagic colitis that had occurred at a nursing home, with O157 identified as the cause. The evidence was mounting, but these were small studies and not always associated with HUS. Still, these papers collectively were suggestive of a connection between E. coli infection (especially with strains that produced the shiga/vero toxin), hemorrhagic colitis, and HUS.

In 1985, a new study came out which really helped to seal the deal. Rather than look only at cases in isolation, the authors designed a case-control study looking at patients with “idiopathic HUS” (in other words, HUS of unknown origin which started with diarrhea, rather than the other variant lacking this symptom). They ended up with 40 patients who qualified. They then picked a single control for each patient, matching them on age, sex, and season of the year. The controls were children either diagnosed with Campylobacter enterocolitis (and therefore, enterocolitis of a known cause) or were healthy children either from a local daycare center, or kids coming in for elective surgeries. Stools were collected from each group and tested for a variety of organisms, including vero toxin-producing E. coli (VTEC, also known as STEC for the shiga-like toxin nomenclature). They also tested for activity of the toxin itself in fecal samples. Finally, in the case patients, attempts were made to collect what are called “acute” and “convalescent” blood samples. These are samples taken when the patient is actually sick (“acute”), and then ones taken a few weeks later (“convalescent), to look at the presence of antibodies in the blood. If it was an infection by the suspected organism (in this case, STEC/VTEC), you should see a rise in antibodies the host produces that target the organism–for these kids, they were looking for antibodies to the shiga/vero toxin.

They found either vero toxin or VTEC in 60% of the case patients, but in none of the controls. Of the VTEC isolated, serotypes included O26, O111, O113, O121, and O157. For the latter, it was the most common type isolated (25% of the VTEC found). Of the patients who were negative for both VTEC and vero toxin, from those who had paired blood samples (12/16 of the remaining cases), 6 did show a rise in antibody titer against the vero toxin–suggesting they had been exposed and were producing antibodies to neutralize the toxin. So, for those keeping score, 75% of the cases had evidence of VTEC infection either by culture or serological techniques. It may not have been the nail in the coffin and there are certainly some flaws (the diversity of controls and lack of analysis of blood titers for the controls being two that pop out at me), but this paper went a long way toward establishing VTEC/STEC as the cause of HUS, which has been subsequently confirmed by many, many studies worldwide.

The most common vehicles of transmission of these organisms have also come into clearer focus since the 1950s, with almost all HUS/STEC outbreaks associated with food products; most common is still the O157:H7 serotype. O157 is a bit unique, in that this strain typically doesn’t ferment sorbitol–as such, this is often used as a diagnostic feature that sets it apart from “normal” E. coli. However, as I mentioned above (and as the current outbreak has shown), a number of other serotypes besides O157:H7 can also cause HUS. Most of these don’t appear to be as commonly associated with outbreaks–rather, they may more commonly cause sporadic disease where fewer people may become sick. Because these don’t have the unique sorbitol-non-fermenting feature, these may be overlooked at a diagnostic lab. There are assays that can detect the Shiga-like toxin directly (actually, we now know there are multiple families of related toxins), but not all labs use these routinely, so it’s likely that the incidence of infection due to non-O157 STEC is higher than we currently know.

HUS was once a mysterious, “complex” disease whose perceived etiology shifted almost overnight, as scientific advances go. What implications does this have for other diseases whose etiology is similarly described as HUS was 50 years ago? More on that tomorrow.

Part Four

As I’ve laid out in parts 1-3, the realization that a fairly simple, toxin-carrying bacterium could cause a “complex” and mysterious disease like hemolytic uremic syndrome came only with 30 years’ of scientific investigation and many false starts and misleading results. Like many of these investigations, the true cause was found due to a combination of hard work, novel ways of thinking, and simple serendipity–being able to connect the dots in a framework where the dots didn’t necessarily line up as expected, and removing extraneous dots as necessary. It’s not an easy task, particularly when we’ve had mostly culture-based methods to rely on since the dawn of microbiology.

If you read start digging around in the evolutionary medicine literature, you’ll see that one oft-repeated tenet is that many more “chronic” and “lifestyle” diseases are actually caused by microbes than we currently realize. (I’ll note that there is active disagreement here in the field–one reason noted is that many of these diseases would decrease one’s fitness and thus they are unlikely to be genetic, but many of them also have onset later in life than the prime reproductive years, so–still controversial). But whether you agree on the evolutionary reasoning or not, I think it’s safe to say that those who make this claim (like the Neese & Williams book I linked) are probably right on the overall assertion that more and more of these “lifestyle/genetics” diseases are going to be actually microbial in cause than we currently realize.

Why do I agree with this claim? History is a great indicator. Many infectious diseases were thought to be due to complex interactions of genetics (or “breeding,” “lineage,” etc.) with “lifestyle.” Think of syphilis and tuberculosis in the Victorian era. Syphilis (and many other diseases which we know now to be sexually-transmitted infections) was considered a disease which affected mainly the lower social classes (“bad breeding”), and was thought to be rooted in both family history as well as an over-indulgence in sex or masturbation. Tuberculosis, because it affected those throughout the income spectrum, was still blamed on “poor constitution” in the lower classes, but was a disease of the “sensitive” and “artistic” in the upper classes. It was also thought to be due to influences of climate in combination with genetics. Or, look to more recent examples of Helicobacter pylori and gastric ulcers, which were also ascribed to dietary habits and stress for a good 30 years before their infectious nature was eventually proven. And from that same era, HIV/AIDS–which even today, some are still all too ready to write off as merely a behavioral disease, rather than an infectious one.

So, we still view many of these diseases of unknown etiology as multi-factorial, “complex” diseases. And undoubtedly, genetic predisposition does play a role in almost every infectious disease, so I’m not writing off any kind of host/pathogen interplay in the development of some of these more rare sequelae, such as HUS as a consequence of a STEC infection. But looking back over history, it’s amazing how many diseases which we view now as having a documented infectious cause were studied for years by researchers thinking that the disease was the result of exposure to a toxin, or diet, or behavior, or a combination of all three.

I’ve mentioned the example of multiple sclerosis in previous posts. Multiple sclerosis is an autoimmune disease; the body produces antibodies that attack and eventually destroy parts of the myelin sheath covering our nerves. The cause of MS, like HUS 40 years ago, is unknown, though it’s thought to be a combination of genetics and environmental influences. Going through the literature, it seems like almost everything has been implicated as playing a causal role at one point or another: pesticides, environmental mercury, hormones, various other “toxins,” and a whole host of microbes, including Chlamydia pneumoniae, measles, mumps, Epstein-Barr virus, varicella zoster (chickenpox), herpes simplex viruses, other herpes families viruses (HHV-6 and HHV-8), even canine distemper virus. They’ve done this looking at both microbe culture (from blood, brain tissue, CNS, etc.) as well as using serology and DNA/RNA amplification in various body sites. None have shown any strong, repeatable links to the development of MS–much like the spurious associations that were seen with adenovirus and HUS.

Although no microbial agent has been convincingly implicated to date, there are tantalizing hints that MS is caused by an infectious agent. There have been “outbreaks” of MS; the most famous occurred in the Faroe Islands in the 1940s. Studies of migrants show that the risks of developing MS seem to be tied to exposures in childhood, suggesting a possible exposure to an infectious agent as a kid. And one of the most common mouse models used to study MS has the disease induced by infection with a virus called Theiler’s murine encephalitis virus (TMEV). If it can happen in mice, why not humans?

It might seem implausible that infection with some microbe could lead to the eventual neurological outcomes of MS, but again, examples abound of weird connections between microbes and health outcomes. For STEC, it might not be intuitively obvious at first glance how a fecal organism could be a cause of kidney failure. The respiratory bacterium Streptococcus pyogenes usually causes throat infections (“strep throat”), but if left untreated, it can also cause kidney damage (glomerulonephritis) or even heart failure due to rheumatic heart disease. A microbial cause of MS could lie in a virus, bacterium, parasite, or fungus–maybe one that we haven’t even discovered yet, but that perhaps will pop up as we learn more and more about our metagenome. Perhaps 30 years down the road, the way we view many of these “complex” diseases will look as short-sighted as it does looking back at old HUS papers from today’s vantage point.

As I’ve laid out this week (part 1, part 2, part 3), the realization that a fairly simple, toxin-carrying bacterium could cause a “complex” and mysterious disease like hemolytic uremic syndrome came only with 30 years’ of scientific investigation and many false starts and misleading results. Like many of these investigations, the true cause was found due to a combination of hard work, novel ways of thinking, and simple serendipity–being able to connect the dots in a framework where the dots didn’t necessarily line up as expected, and removing extraneous dots as necessary. It’s not an easy task, particularly when we’ve had mostly culture-based methods to rely on since the dawn of microbiology.

If you read start digging around in the evolutionary medicine literature, you’ll see that one oft-repeated tenet is that many more “chronic” and “lifestyle” diseases are actually caused by microbes than we currently realize. (I’ll note that there is active disagreement here in the field–one reason noted is that many of these diseases would decrease one’s fitness and thus they are unlikely to be genetic, but many of them also have onset later in life than the prime reproductive years, so–still controversial). But whether you agree on the evolutionary reasoning or not, I think it’s safe to say that those who make this claim (like the Neese & Williams book I linked) are probably right on the overall assertion that more and more of these “lifestyle/genetics” diseases are going to be actually microbial in cause than we currently realize.

Why do I agree with this claim? History is a great indicator. Many infectious diseases were thought to be due to complex interactions of genetics (or “breeding,” “lineage,” etc.) with “lifestyle.” Think of syphilis and tuberculosis in the Victorian era. Syphilis (and many other diseases which we know now to be sexually-transmitted infections) was considered a disease which affected mainly the lower social classes (“bad breeding”), and was thought to be rooted in both family history as well as an over-indulgence in sex or masturbation. Tuberculosis, because it affected those throughout the income spectrum, was still blamed on “poor constitution” in the lower classes, but was a disease of the “sensitive” and “artistic” in the upper classes. It was also thought to be due to influences of climate in combination with genetics. Or, look to more recent examples of Helicobacter pylori and gastric ulcers, which were also ascribed to dietary habits and stress for a good 30 years before their infectious nature was eventually proven. And from that same era, HIV/AIDS–which even today, some are still all too ready to write off as merely a behavioral disease, rather than an infectious one.

So, we still view many of these diseases of unknown etiology as multi-factorial, “complex” diseases. And undoubtedly, genetic predisposition does play a role in almost every infectious disease, so I’m not writing off any kind of host/pathogen interplay in the development of some of these more rare sequelae, such as HUS as a consequence of a STEC infection. But looking back over history, it’s amazing how many diseases which we view now as having a documented infectious cause were studied for years by researchers thinking that the disease was the result of exposure to a toxin, or diet, or behavior, or a combination of all three.

I’ve mentioned the example of multiple sclerosis in previous posts. Multiple sclerosis is an autoimmune disease; the body produces antibodies that attack and eventually destroy parts of the myelin sheath covering our nerves. The cause of MS, like HUS 40 years ago, is unknown, though it’s thought to be a combination of genetics and environmental influences. Going through the literature, it seems like almost everything has been implicated as playing a causal role at one point or another: pesticides, environmental mercury, hormones, various other “toxins,” and a whole host of microbes, including Chlamydia pneumoniae, measles, mumps, Epstein-Barr virus, varicella zoster (chickenpox), herpes simplex viruses, other herpes families viruses (HHV-6 and HHV-8), even canine distemper virus. They’ve done this looking at both microbe culture (from blood, brain tissue, CNS, etc.) as well as using serology and DNA/RNA amplification in various body sites. None have shown any strong, repeatable links to the development of MS–much like the spurious associations that were seen with adenovirus and HUS.

Although no microbial agent has been convincingly implicated to date, there are tantalizing hints that MS is caused by an infectious agent. There have been “outbreaks” of MS; the most famous occurred in the Faroe Islands in the 1940s. Studies of migrants show that the risks of developing MS seem to be tied to exposures in childhood, suggesting a possible exposure to an infectious agent as a kid. And one of the most common mouse models used to study MS has the disease induced by infection with a virus called Theiler’s murine encephalitis virus (TMEV). If it can happen in mice, why not humans?

It might seem implausible that infection with some microbe could lead to the eventual neurological outcomes of MS, but again, examples abound of weird connections between microbes and health outcomes. For STEC, it might not be intuitively obvious at first glance how a fecal organism could be a cause of kidney failure. The respiratory bacterium Streptococcus pyogenes usually causes throat infections (“strep throat”), but if left untreated, it can also cause kidney damage (glomerulonephritis) or even heart failure due to rheumatic heart disease. A microbial cause of MS could lie in a virus, bacterium, parasite, or fungus–maybe one that we haven’t even discovered yet, but that perhaps will pop up as we learn more and more about our metagenome. Perhaps 30 years down the road, the way we view many of these “complex” diseases will look as short-sighted as it does looking back at old HUS papers from today’s vantage point.

As I mentioned yesterday, the epidemiology of hemolytic uremic syndrome (HUS) was murky for several decades after it was first defined in the literature in 1955. In the ensuing decades, HUS was associated with a number of infectious agents, leading to the general belief that it was a “multifactorial disease”–one that had components of genetics and environment, much like we think of multiple sclerosis today, for example.

Several HUS outbreaks made people think twice about that assumption, and look deeper into a potential infectious cause. A 1966 paper documented the first identified outbreak of HUS, which occurred in Wales. The researchers examined a number of possible environmental factors the patients may have had in common–including food, water, and various toxins–but came up empty. They sum up:

Since it is almost invariably preceded by a gastrointestinal or respiratory illness, it seems probable that it represents a response to an infection. Although Gianantonio et al. (1964) have identified one possible causative virus, it may be that various infective agents can initiate the syndrome.

This idea held throughout the next 20-odd years, as numerous studies looked at both environmental and genetic effects that may be leading to HUS. A 1975 paper examined HUS in families, suggesting that there may be two types of HUS (which we now know to be true–the genetic form is less often associated with diarrhea, and tends to have a worse prognosis as I mentioned yesterday). But still, no definitive cause for either.

There were also a number of studies testing individuals for many different types of pathogens. A 1974 paper enrolled patients in the Netherlands between 1965 and 1970, but one of the inclusion criteria was a “history of a prodromal illness in which gastrointestinal or respiratory tract symptoms were present.” The respiratory tract symptoms are mentioned in a number of papers, and were probably a red herring that sent people in search of the wrong pathogens for awhile. In this particular paper, they examined children for infection with a number of viral and bacterial pathogens, using either culture or serological methods (looking for antibodies which may suggest a recent infection). In that portion of the paper, they note a possible association with adenoviruses, but state that the data don’t support a bacterial infection–a viral etiology was deemed more likely. Regarding basic epidemiology, they did note a few small clusters of cases in families or villages, as well as a peak in cases in spring/summer–as well as an increasing number of cases from the first year of their study to the last. The epidemiology of HUS was starting to become clearer, and the syndrome appeared to be on the rise.

Even as additional case reports occasionally targeted foods as a precursor to HUS outbreaks, it wasn’t until the late 1970s and early 1980s that HUS really started to come into focus. In 1977, a paper was published identifying the “Vero toxin”–a product of E. coli that caused cytotoxicity in Vero cells (a line of African green monkey kidney cells, commonly used in research). Researchers were closing in.

As with many infectious diseases, there are potential lingering sequelae of infection, which can occur weeks to years after the acute infection has cleared up. Like almost 800 others involved in this outbreak, the woman who unwittingly infected others via food developed hemolytic uremic syndrome, or HUS. We now know that the most common cause of HUS are bacteria such as STEC (“shiga toxin-producing E. coli“); the “shiga toxin” that they produce inhibits protein synthesis in the host and cause cell death. This can have systemic effects, and leads to clotting in affected organs–most commonly the kidneys, but other organs can also be affected. Dialysis may be necessary, and the infection can lead to kidney failure and the need for organ transplantation. There is already concern that, because of the huge numbers of HUS cases, many patients will have long-term kidney damage, including the potential need for additional organs (and possibly, re-vamping the way donations are made as well):

In previous E. coli outbreaks, up to half of patients who developed the kidney complication were still suffering from long-term side effects 10 to 20 years after first falling sick, including high blood pressure caused by dialysis.

In addition to possible kidney problems, people who have survived serious E. coli infections may also suffer from neurological damage, as the bacteria may have eaten away at blood vessels in the brain. That could mean suffering from seizures or epilepsy years after patients recover from their initial illness.

While it’s common knowledge in the medical community now that STEC can lead to HUS, which can lead to chronic kidney issues, for many years, the link between E. coli and HUS was obscured. HUS first appears in the literature in 1955, but the link to STEC wasn’t confirmed until the early 1980’s. In the interim, myriad viruses and bacteria were examined, as well as genetic causes. (There are cases of HUS caused by host mutations and other etiologies, but they are much less common than HUS caused by STEC and related organisms). In future posts this week, I’ll delve into the history of HUS and look at a few studies which examined alternative hypotheses of causation, until finally STEC was confirmed as the causative agent. I’ll also discuss what this means as far as discovering infectious causes of other “complex” and somewhat mysterious diseases whose causes are unknown, as HUS was a mere 30 years ago.